Tumors are new creatures formed in the body due to actions of a variety of oncogenic factors and the following changes of genetic material of cells resulting in abnormal gene expression and cell proliferation. The tumor cells lose their normal growth regulatory function and have autonomous or relatively autonomous growth ability. The tumor cells can continue to grow even the oncogenic factors disappear and will cause a consumption of large quantities of human's nutrients. If not being found and treated early, the cancer cells will be transferred and grow throughout the body, and release a variety of toxins that cause the body weight loss, anemia, organ failure and even death.
The method of treating tumors mainly includes three aspects: drug therapy, surgery and radiation therapy. Drug therapy is becoming increasingly important in cancer treatment since surgery and radiation therapy are difficult to eradicate the tumor and fail to show obvious effect in patients with the mid-advanced cancer.
Conventional anticancer drugs do not distinguish between tumor cells and normal cells, and often cause serious side effects. Targeted drugs specifically target to cancer cells and can accurately act on the tumor, which greatly improves the level of treatment and reduces the adverse response rate, such as making the median survival time of patients with advanced colorectal cancer increased 66.7%, and the efficiency of the treatment of advanced breast cancer increased 71.3%.
As pharmaceutical companies are accelerating the development of targeted antineoplastic drugs, and there is a great market demand for this class of antineoplastic drugs, molecular targeted drugs have become the world's fastest growing unit in the worldwide market. PI3K pathway is the most common place where human cancer cells mutate, and it can lead to cell proliferation, activation and signal amplification. PI3K and mTOR are important kinases of PI3K signaling pathway.
PI3K is a member of lipid kinase family, it regulates cell metabolism and growth through phosphorylation at 3-position of phosphatidylinositol to produce phosphatidylinositol-triphosphate (PIP3). This PIP3, which is the second messenger of lipid, can make P13K paired with downstream effectors (especially Akt), resulting in membrane recruitment and phosphorylation, cell proliferation and activation. Therefore, inhibition of phosphatidylinositol 3-kinase can affect the PI3K pathway, thereby inhibiting cancer cell proliferation and activation.
mTOR is a serine/threonine protein kinase present in the cytoplasm, it belongs to the phosphoinositide 3-kinase-related protein kinase family and exists in organism as two complexes forms, namely mTORC1 (rapamycin target) and mTORC2 (not inhibited by rapamycin). mTOR is a cellular signal transduction protein, which regulates the response of tumor cells to nutrients and growth factors, and controls tumor blood supply through the role of vascular endothelial growth factor. mTOR inhibitors can make cancer cells starved, and reduce the tumor volume by inhibiting mTOR.
Now PI3K and/or mTOR inhibitors have been developed as medicament, but no inhibitor goes to the market. The prior art literature, Journal of Medicinal Chemistry (2011), 54(5), 1473-1480, “Discovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer, discloses a compound named as Torin2 and reports the study result about its in vivo pharmacokinetics.

For the study of the kinase inhibitor (including PI3K and/or mTOR inhibitors), a great attention should be paid to the selectivity on the kinase target. Since the kinase has a high homology, a small compound can inhibit other kinase targets while it inhibits PI3K and/or mTOR. These kinases play important roles in the biosignal conduction. Once they are inhibited, the signal conduction disorder will appear, showing the harmful adverse effect or toxicity to the body. Therefore, it is urgently needed for the PI3K and/or mTOR kinase to develop the kinase inhibitor having good selectivity.
Besides the kinase selectivity, the selectivity on other non-kinase target is also significant. The non-kinase targets such as ion channel and various acceptors are also important for the physiological process such as the signal conduction and the neurotransmitter release. Once these non-kinase targets are inhibited, the body will have metabolic disturbance and physiological function impairment, which can bring a serious influence on the safety of the patient.
In summary, it becomes a hotspot in the current study of antitumor drug to develop a compound having a high selectivity on P13K and/or mTOR, a good inhibitory activity and a good pharmacokinetics.